al. 1997).
Aplicações de formas variantes da PCR também são interessantes no estudo de tratamentos com a terapia hormonal. As respostas para a terapia unti-androgênica e a expressão do RNAm do KLK2 sao correlacionadas, em contraste com a do KLK3, indicando que o KLK2 é um marcador para o
screening correto do câncer de próstata (Kawakami et al. 1997). Contudo,
existem controvérsias quanto a presença e a quantidade de expressão desses marcadores quando comparados indivíduos hormonio-dependentes com hormônio-independentes (Ylíkoski etal. 2001, Ylikoski et al. 2QQ2).
Apesar dos resultados animadores apontados acima deve ficar claro que as técnicas de biologia molecular não são capazes somente de detectar células tumorais prostáticas com potencial metastático, mas também células que não têm este potencial gerando o falso-positivo (Sokoloff et al. 1996).
3.6. Expressão Tecidual dos genes KLK2 e KLK3
A concentração do RNAm do KLK2 corresponde de 10% a 60% da concentração do RNAm do KLK3 em tecido prostático humano (Chapdelaine
et al. 1988, Henttu et al. 1990, Young et al. 1992). Contudo essas expressões
expressão dos genes KLK2 e KLK3 em tecido prostático com anomalias de forma ambígüa.
O gene KLK3 parece ser mais expresso em tecidos benignos quando comparados com malignos (Pretlow et al. 1991, Darson et al. 1997, Herrala et
al. 2001, Magklara et al. 2000a, Qiu el al. 1990), além disso acredita-se que
as baixas expressões do KLK3 em tecido tumoral estão associadas com o desenvolvimento de tumores potencialmente mais agressivos (Stege et al. 2000). Entretanto outros trabalhos mostram que não existe diferença de expressão do gene KLK3 em tecidos com as patologias CaP e HPB (Gallee et
al. 1990, Henttu et al. 1990, Hakalahti et al. 1993). Contudo, Darson e
colaboradores (1999) detectaram por imunohistoquímica, usando anticorpos mono e policlonais, maiores concentrações de PSA em tecido tumoral que em benigno e sugeriram que os resultados ambíguos de expressão se devem às reações cruzadas entre o PSA e a 11K2 produzidas por anticorpos policlonais.
n VTK3 a expressão do KLK2 tem resultados
Assim como o klax p
controversos, estudos imunohistoquímicos apontam a superexpressão do gene sindico do câncer de próstata (Darson et al. 1997, 1999,
com o avanço patologico ao vmi
Herrala et al. 2001) Entretanto, foi encontrada maior expressão para o gene em tecido benigno comparado com o maligno (Magklara et u/.2000a), já Henttu e colaboradores (1990) apontam nenhuma diferença de expressão para o gene em tecido benigno comparado com o mahgno.
Para explicar estes resultados dúbios várias especulações são • • o Jrfprpneas discrepantes entre os níveis de RNAm e propostas. Primeiro, as direrença
j-r Mrnicas talvez possam ser explicadas devido proteíco obtidos por diferentes técnicas, p
,,„m em tecidos tumorais, que possam mascarar epitopos a eventos, que ocorrem em i
^nnhecimento de anticorpos (Herrala et rz/.2001). Tais importantes para o reconhecimento
eventos incluem processamentos heterogêneos na região N-termmal gerando isoformas (Herrala et al. 1998 apud Herraía et u/,2001) e rrreguiares
30
glicosilações proteicas (Huber et al.\995 apttd Herraia et «72001). Segundo, como a 11K2 ativa a pró-forma do PSA (Kumar et al. 1997, Lõvgren et al.
1997, Takayama et al. 1997) e este tem função de supressor de tumor
(Diamandis et al. 2000a, Diamandis 2000), talvez altas concentrações da hK2
induzam a ação do PSA para impedir a progressão do tumor (Herraia et «72001). Entretanto, ao mesmo tempo as bmxas expressões do K.LK3 com o avanço do câncer de próstata podem estar associadas com o perda da sua função de supressor de tumor (Magkalara et al. 2000a).
3.7. Regulação Hormonal dos genes KLI<2 e KLK3
Tanto KLK2 como o KLK3 são hormonalmente regulados por , , 199? Murtha et al. 1993). Entretanto, a regulação androgenos (Young et al. iyy~,
da expressão desses genes não é apenas medrada por androgenos, mas também por fatores autócrinos e parácrmos sugerindo um mecanismo de ■tn rnmnlexo (Young et al. 1995, Sadar et al. 1999).
controle de expressão muito complexo t oi b
• ~ ovnrpqsão dos genes na próstata indicam uma Além disso, vanações na expressão aos g
regulação drferenciada desses genes (Darson el al. 1999). Diferentes linhagens celulares tumorais de mama exibrram padrões de expressão distintos para vários receptores nucleares co-reguladores e é possível que os níveis relativos de expressão desses co-ativadores ou co-repressores possam diferencialmente modular a atividade transcricional do AR dentro da região
, h o p KLK3 (Magklara et al. 2002).
promotora dos genes KLK2 e klk t
, nossui três AREs (elementos de resposta a O promotor do KLK3 possui
, • nl 1991b Cleutjens et al. 1996, Schuur et al. 1996) androgenos) (Riegman et al. 1 o, J
. r? HnR AREs (Riegman et al. 1991a, Murtha et al. 1993,
c o promotor do KLK2 dois At t
Magklara el al 7000b). Esses AREs são necessários para a regulação posttiva dos genes por androgenos mostrados m vitro em linhagens celulares tumorais prostáticas na região 5’ do promotor (Murtha et al. 1993). Entretanto, foram
encontrados outros elementos de resposta a bormomos esteroides, aderentes do andrógeno, próximos a região promotora dos genes oferecendo bases moleculares para a expressão desses genes em tecidos extra prostáticos que tenham receptores de esteróides (Shan ct al. 1997).
Há evidências de que os AREs do KLK2 têm maior resposta androgênica que os AREs do KLK3 sugerindo que existem outras regiões regulatórias do promotor do KLK3, pois a quantidade de RNAm desse gene é bem superior ao do KLK2 (Rittenhouse et al. 1998). Além disso, o KLK2 e o
K.LK.3 são superexpressos em linhagens celulares lumorats prostáttcas andrógenos dependentes comparadas com andrógenos rndependentes (Riegman et al. 1991a, Vaarala et al- 2000). Uma das principais diferenças
j p não androgênicas em linhagens celulares entre as respostas androgenicas e nao anu^t,
oconra efetiva do receptor de andrógeno em células tumorais prostáticas e a presença etenva uu E
/rv- nl 1991a 1991b), bem como a presença hormônio dependentes (Riegman et al. 1991 a,
, ■ 1 do AR capazes de ativar esses genes (Sadar et de outras vias, independentes a
32
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